Gender-Specific Treatment of Pediatric Cardiac Arrest

小儿心脏骤停的性别针对性治疗

基本信息

批准号：
7189910
负责人：
Robert S B Clark
金额：
$ 24.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7189910
关键词：
Acetylcysteine Acute Address Adolescent Adult Affect Age Apoptosis Apoptosis Promoter Apoptotic Asphyxia Attenuated Behavioral Biochemical Brain Brain Injuries Brain Ischemia Cardiac Cardiopulmonary Arrest Caspase Caspase Inhibitor Cell Death Cessation of life Child Childhood Chronic Clinical Clinical Trials Clinical Trials Design Coma Complement Condition Coupled Cysteine Data Disease End Point Equilibrium Esters Etiology Evaluation Female Foundations Gender Glutamic Acid Glutathione Glutathione Metabolism Pathway Glycine Gonadal Steroid Hormones Guidelines Harvest Heart Arrest Heart failure Hippocampus (Brain)Human Hypoxemia Impairment In Vitro Infant Intervention Invasive Investigation Ischemia Knowledge Measures Mediating Metabolism Methods Modeling Molecular Morbidity - disease rate Motor Nerve Degeneration Neurologic Neurological outcome Neurons Numbers Organ Outcome Outcome Assessment Outcome Study Pathway interactions Patients Peroxonitrite Physiologic Monitoring Physiological reperfusion Predisposition Principal Investigator Rate Rattus Reduced Glutathione Reperfusion Therapy Research Proposals Resuscitation Rodent Sex Characteristics Sexual Maturation Short-Term Memory Signal Transduction Staurosporine Stress Survivors Testing Therapeutic Therapeutic Effect Translating Treatment Efficacy United States United States National Institutes of Health age group boys caspase-2 clinically relevant cohort cytotoxicity day design functional outcomes girls improved in vivo in vivo Model injured innovation male mortality natural hypothermia neonatal hypoxic-ischemic brain injury neuron loss neuronal survival neuroprotection novel postnatal pre-clinical prevent programs rehabilitation strategy response sex tool

项目摘要

DESCRIPTION (provided by applicant): Cardiopulmonary arrest in infants and children remains a significant cause of morbidity and mortality. The principle factor influencing outcome in survivors of cardiopulmonary arrest is the neurologic sequelae resulting from hypoxic-ischemic encephalopathy, unfortunately, there are no interventions to reverse the cellular consequences of hypoxic-ischemic encephalopathy. A clinically relevant model of pediatric asphyxial cardiac arrest in postnatal day 17 rats has been developed that has the capacity for invasive physiologic monitoring and resuscitation that mimics guidelines used in humans, biochemical and cellular assessment, and acute and long-term functional outcome assessment with the potential for application of rehabilitation strategies. Preliminary data show key gender differences in glutathione metabolism and activation of apoptotic cascades in the injured brains of juvenile rats after asphyxia and neurons in culture, implying that pathways leading to neurodegeneration and ultimate cell death and survival may be different between sexes. This is of paramount importance because in the present day infants and children are treated similarly after cardiopulmonary arrest whether they are boys or girls, and both genders are affected by this clinical entity in similar proportions. To our knowledge the influence of gender in the pathobiology of hypoxic-ischemic encephalopathy after cardiopulmonary arrest prior to sexual maturation has not been thoroughly addressed. Using this in vivo model of asphyxial cardiopulmonary arrest in juvenile rats, coupled with parallel in vitro studies, the hypothesis that global hypoxemia-ischemia/reperfusion initiates gender specific cell death pathways and reversible neurological impairments will be tested. Specific Aims are designed to determine whether neuroprotection can be achieved using novel therapies specifically targeting glutathione depletion and apoptosis, and whether therapeutic efficacy is gender-dependent. Dismal outcomes seen in infants and children after cardiopulmonary arrest and the resultant societal impact warrant rigorous pre-clinical testing in a clinically relevant model. The primary objective of this research proposal is to identify efficacious and gender-specific the clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest and gender-specific, therapeutic strategies, to serve as the foundation for clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest.

描述（由申请人提供）：婴儿和儿童的心肺停滞仍然是发病率和死亡率的重要原因。不幸的是，由于缺氧 - 缺血性脑病导致的神经系统后遗症影响了心肺停滞幸存者的主要因素，但不幸的是，没有干预措施可以逆转低氧 - 异化性脑病的细胞后果。已经开发了出生后第17天的小儿窒息心脏骤停的临床相关模型，该模型已开发出具有侵入性生理监测和复苏的能力，这些模拟能力模仿了人类，生物化学和细胞评估的指南，以及急性和长期功能评估，并具有施加型施用替代策略的可能性。初步数据表明，在窒息和培养中神经元之后，青少年大鼠受伤的大脑受伤的大脑中凋亡级联反应的关键性别差异以及培养中的凋亡级联反应，这表明这种途径会导致神经变性和最终的细胞死亡，并且性别之间可能是不同的。这至关重要，因为在当今的婴儿和儿童在心肺逮捕后类似地对待儿童，无论他们是男孩还是女孩，并且两种性别都受到该临床实体的影响。据我们所知，在性成熟之前，心肺停滞后性别的性别缺氧性脑病病理生物学的影响尚未得到彻底解决。使用这种体内模型的少年大鼠中进入的心肺心肺停滞，再加上平行的体外研究，这是全球低氧血症 - 缺血/再灌注的假说，可以启动性别特定的细胞死亡途径和可逆的神经系统障碍。特定目的旨在确定使用专门针对谷胱甘肽耗竭和凋亡的新疗法可以实现神经保护作用，以及治疗疗效是否取决于性别依赖性。心肺停滞后的婴儿和儿童在儿童中的惨淡结果以及由此产生的社会影响保证了临床相关模型中严格的临床前测试。这项研究建议的主要目的是确定旨在改善心肺停滞和性别特异性，治疗策略后婴儿和儿童的临床试验的临床试验，以作为旨在改善心脏肺后婴儿和儿童预后的临床试验的基础。